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Finding Monkey Moon
Every night at half past seven, Michael and his stuffed monkey go hippity-hop, hippity-hop, up the stairs to bed. But one night when Michael calls out for Monkey Moon, he's not in any of his favorite places. Dad thinks he must still be at the park, so he and Michael bundle up and head outside, into the dark street, to retrace their steps.
Book
Holistic Review: Math Anxiety and the STEM Profession
Demand for STEM professionals in the US is growing. However, some students interested in becoming STEMpnfessionals find math anxiety (MA) a barrier to success. STEM prefessionals, such as mathematicians, engineers, and natural scientists, dipend heavily on theoretical mathematics, while social scientists and technologists dipend on practical applications if mathematics. This may be a sign.ficant consideration when students choose a STEM major and decide whether to remain in that major. MA a, p pears to be a factor in degree selection and retention. A search if peer-reviewed sources using \"mathematics anxiety\" and \"sef-ijficaiy\" was narrowed to the most relevant research for postsecondary populations. The author mined the five most cited sources' references to gain a \"genealogy\" if MA research. These were sorted by date, education level, STEM population, and methods. Past MA research has heavily di pended on convenience sampling, primarily resultingin student populations from social science (such as psychology) and mathematics or were not d.fferentiated by major. There is a sign.ficant dificit if data on MA in engineering and technology majors. There has also been limited exploration if the salient variables contributing to MA in these students through qualitative research. Ho pl: os AMAS test instrument is the appropriate methodfior measuring MA in this population. A demonstrated connection exists between MIA and math sef-tjficaiy, perceived math value, and perceived control over the math assessment outcome. The proposed conceptual framework uses Bandura's Sef-Tjficaty Theory (SET) and Pekrun's ControlValue Theory (CVT) to develop subsequent research.
Journal Article
Increasing Share of Practicing Female Family Physicians, 2010-2020
The growing role of women in family medicine is increasingly apparent—more than 50% of U.S. medical students are women, and higher shares of women are entering and graduating from family medicine residency programs. On average, female family physicians work different hours and may deliver care differently than male family physicians. Thus, understanding the changing composition of the family medicine workforce is critical for creating sustainable workforce policies and assessing patient care.
Journal Article
Ensuring Primary Care Access in States with an Aging Family Physician Workforce
The United States depends on a robust primary care workforce to achieve the Institute for Healthcare Improvement Triple Aim goal of population health delivered at lower cost and with an improved patient care experience. With nearly 40% of U.S. family physicians older than 55 years, policymakers should support broad-spectrum training models that produce enough primary care physicians to meet state population needs.
Journal Article
Dendrimer-Conjugated nSMase2 Inhibitor Reduces Tau Propagation in Mice
Alzheimer’s disease (AD) is characterized by the progressive accumulation of amyloid-β and hyperphosphorylated tau (pTau), which can spread throughout the brain via extracellular vesicles (EVs). Membrane ceramide enrichment regulated by the enzyme neutral sphingomyelinase 2 (nSMase2) is a critical component of at least one EV biogenesis pathway. Our group recently identified 2,6-Dimethoxy-4-(5-Phenyl-4-Thiophen-2-yl-1H-Imidazol-2-yl)-Phenol (DPTIP), the most potent (30 nM) and selective inhibitor of nSMase2 reported to date. However, DPTIP exhibits poor oral pharmacokinetics (PK), modest brain penetration, and rapid clearance, limiting its clinical translation. To enhance its PK properties, we conjugated DPTIP to a hydroxyl-PAMAM dendrimer delivery system, creating dendrimer-DPTIP (D-DPTIP). In an acute brain injury model, orally administered D-DPTIP significantly reduced the intra-striatal IL-1β-induced increase in plasma EVs up to 72 h post-dose, while oral DPTIP had a limited effect. In a mouse tau propagation model, where a mutant hTau (P301L/S320F) containing adeno-associated virus was unilaterally seeded into the hippocampus, oral D-DPTIP (dosed 3× weekly) significantly inhibited brain nSMase2 activity and blocked the spread of pTau to the contralateral hippocampus. These data demonstrate that dendrimer conjugation of DPTIP improves its PK properties, resulting in significant inhibition of EV propagation of pTau in mice. Dendrimer-based delivery of DPTIP has the potential to be an exciting new therapeutic for AD.
Journal Article
Disease modifying biomaterials for modulating mechanical allodynia in a preclinical model of rheumatoid arthritis
Pain is a key symptom associated with rheumatoid arthritis (RA) and can persist even in the context of overall disease control by standard‐of‐care disease modifying anti‐rheumatic drugs (DMARDs). Analgesic agents and corticosteroids are often used to supplement DMARDs for pain relief but lack disease modifying properties, and their sustained use carries adverse risks. In this work, we characterized the progression of pain sensitivity in the SKG mouse model of RA and evaluated the potential therapeutic interventions. Male and female SKG mice, after systemic mannan injection, developed a mechanical pain phenotype and joint swelling, with a strong inverse correlation between clinical arthritis scores and pain thresholds. To test potential interventions for pain alleviation, we evaluated all‐trans retinoic acid (ATRA)‐loaded poly(lactic‐co‐glycolic acid) microparticles (ATRA‐PLGA MP) administered via intra‐articular injection, which we have previously demonstrated to be disease‐modifying. The pain and inflammation patterns assessed by the von Frey test and clinical scoring showed ATRA‐PLGA MP monotherapy reduced inflammation and alleviated mechanical allodynia in arthritic SKG mice, an effect that was amplified by combination treatments with standard‐of‐care agents. In early‐stage arthritis, co‐administration with cytotoxic T‐lymphocyte‐associated protein (CTLA)‐4‐Ig, clinically known as abatacept, delayed disease progression and sustained the reduction of mechanical allodynia. In established arthritis, sequential treatment with the corticosteroid dexamethasone (Dex) reduced cumulative disease burden and reduced mechanical allodynia. These findings highlight the potential of combining ATRA‐PLGA MP with standard‐of‐care treatments as a potential strategy to enhance the efficacy and durability of disease modification and pain alleviation for arthritis management.
Journal Article
Proportional Erosion of the Primary Care Physician Workforce Has Continued Since 2010
We estimate that 217,208 primary care physicians provided direct patient care in the United States in 2018. This represents an even lower percentage (30%) of the total U.S. physician cohort than the 2010 Council on Graduate Medical Education's (COGME's) recommendation to increase primary care to 40% of the overall physician workforce.
Journal Article
Dendrimer-Conjugated Glutamine Antagonist, D-TTM020, Ameliorates Brain Immune Dysregulation and Improves Neurobehavioral Deficits in the Mecp2-Deficient Mouse Model
Rett Syndrome (RTT) is a neurodevelopmental disorder characterized by mutations in the MeCP2 gene, predominantly affecting females. Recent work with MeCP2-deficient mouse models showed a significant role in glutamatergic transmission, specifically microglia-produced glutamate and glutaminase upregulation, in RTT pathology. The glutamine antagonist 6-diazo-5-oxo-L-norleucine (DON) is a potent glutaminase inhibitor; however, its use is limited due to systemic toxicities arising from its non-specific inhibition of glutamine-utilizing reactions. In this work, we determined whether dendrimer conjugation of a DON analog, TTM020 (or D-TTM020), results in targeted microglial glutaminase inhibition and behavioral changes in Mecp2 KO and heterozygous mice upon systemic administration. D-TTM020 at 1 mg/kg (drug basis) selectively and significantly inhibits glutaminase enzyme activity in the microglia of Mecp2 KO mice. Biweekly systemic treatment with 1 mg/kg of D-TTM020 improved the neurobehavioral phenotype in symptomatic Mecp2 KO and het mice. D-TTM020 also restored long-term retrieval of conditioned fear memory and improved cue responses during fear extinction after 8 weeks of treatment in symptomatic Mecp2 het mice. Our data indicate that selectively targeting glutamine metabolism in dysregulated glia using dendrimers represents a promising strategy that may offer a therapeutic approach for addressing glutamate dysregulation in RTT.
Journal Article
Immunomodulatory Nanoparticles Enable Combination Therapies To Enhance Disease Prevention and Flare Control in Rheumatoid Arthritis
Disease-modifying antirheumatic drugs (DMARDs) have greatly improved the treatment of rheumatoid arthritis (RA), but strategies to prevent disease onset and recurring flares remain limited. While abatacept (CTLA-4 IgG) can delay RA onset and corticosteroids are used for flare control, the benefit is temporary. We report that combining standard-of-care treatments with a locally administered immunomodulatory agent, termed Agg-CLNP, enhances both disease prevention and flare mitigation. Agg-CLNP consists of polymer nanoparticles conjugated with an immunodominant aggrecan peptide and encapsulate calcitriol. These nanoparticles are optimized for uptake by dendritic cells (DC) in lymph nodes proximal to arthritic joints. In vitro, Agg-CLNP suppressed costimulatory molecules and HLA class II (HLA-2) expression and upregulated CTLA-4 in human monocyte-derived DC from healthy and RA donors. In SKG mice, a T cell-driven RA model, Agg-CLNP combined with CTLA-4 IgG synergistically delayed disease onset and reduced severity. In a dexamethasone (Dex) withdrawal flare model, post-Dex Agg-CLNP treatment reduced flare severity and preserved a regulatory phenotype in DC, while suppressing local pathogenic TH17 cells. Next generation RNA sequencing of lymph node DC revealed Ctla4 upregulation and changes in other immunomodulatory genes linked to flare prevention. These findings highlight Agg-CLNP as a potential therapeutic strategy to address critical unmet needs in RA management.
Journal Article